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Dynamic Post-Translational Control of HDAC Activity in Breast Cancer and Implications for Drug Discovery

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posted on 25.07.2018 by Thomas Hanigan
Histone deacetylase (HDAC) activity is regulated by formation of co-regulator complexes and post-translational modification. Whether these mechanisms are transformed in cancer and how this affects the binding and selectivity of HDAC inhibitors (HDACi) is unclear. In this work, we developed a set of methods, based on photoreactive HDAC inhibitor probes (PRPs), to determine how post-translational regulation of HDAC activity affects inhibitor binding in situ. Using these methods we show that phosphorylation of several HDAC isoforms plays a key role in regulating inhibitor binding and selectivity in a cell-typed dependent manner. Of particular importance, we find that phosphorylation of HDAC3 by c-Jun N-terminal kinase (JNK) plays an important role in regulating HDAC3-inhibitor binding and enzyme activity in aggressive triple-negative breast cancer cell lines (TNBC), suggesting this enzyme could be a pertinent target for this disease state. We also show that several breast cancer cell lines exert a post-translational feedback mechanism on HDAC activity in response to potent HDAC inhibitors and provide evidence that this is plays an important role in HDACi mechanism of action.

History

Advisor

Petukhov, PavelFrasor, Jonna

Chair

Petukhov, Pavel

Department

Medicinal Chemistry and Pharmacognosy

Degree Grantor

University of Illinois at Chicago

Degree Level

Doctoral

Committee Member

Moore, Terry Thatcher, Gregory Mahmud, Nadim Grayson, Dennis

Submitted date

May 2018

Issue date

07/02/2018

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